CBR-1 Benefit/Risk Assessment for Use of Clozaril in the Treatment of Emergent Suicidal Behavior John M. Kane, MD Chairman, Department of Psychiatry The Zucker Hillside Hospital The North Shore–Long Island Jewish Health System Professor of Psychiatry, Neurology and Neuroscience Albert Einstein College of Medicine C

CBR-2 Benefit and Risk for Treatment of Suicidal Behavior Benefits Risks Reduction of Suicidal Behavior Treatment Intervention

CBR-3 Clozaril ® Clinical Uses  First approved in 1969 for treatment of schizophrenia  Plays unique role in management of treatment- resistant and partially-responsive patients  Increased interest in other clinical uses eg, substance abuse, smoking cessation, movement disorders, aggression, suicidal behavior

CBR-4 The Burden of Suicidal Behavior Untreated suicidal behavior leads to increased  Morbidity and mortality  Hospitalizations (psychiatric or medical)  Emergency room visits  Interventions to prevent suicide attempts – Concomitant medication – Increased surveillance  Family burden  Societal costs

CBR-5 InterSePT as Basis for Benefit/Risk Assessment of Clozaril ®  Well-designed, prospective, randomized study  Endpoints are objectively determined by blinded SMB  Compares 2 atypical antipsychotics  Long-term (2 years) efficacy and safety assessments  Procedures designed to maximize patient safety C

CBR-6 Results of WLW and Cox’s Analyses Hazard ratio 95% CI P value WLW.031 Cox’s proportional hazard analysis § Type 1 || , Hazard ratio 95% CI P value WLW.031 Cox’s proportional hazard analysis § Type 1 || , CSR Table 9-1 §Protocol specified full model. ||Suicide attempts or hospitalizations to prevent suicide.

CBR-7 Kaplan-Meier Estimates of Cumulative Probabilities of a Suicide Attempt or Hospitalization to Prevent Suicide 32% 24% C Clozaril ® Zyprexa ® P =.0195

CBR-8 Clinically Meaningful Outcomes CSR Table 9-5 C §Fisher’s exact test. P <.008 § P <.026 § P <.013 § P <.046 § (adverse events)

CBR-9

CBR-10 Clinical Risks of Intervention  Agranulocytosis – Current estimated incidence in US is 0.3% during first year of treatment – Well-established risk management system  Myocarditis – Current rate in US is 5 per 100,000 patient years  Seizures – Incidence 3%  Weight gain and disturbances in glucose regulation

CBR-11 InterSePT Risk Experience With Clozaril ®  Adverse event profile generally consistent with previous clinical experience  No cases of agranulocytosis, myocarditis, or cardiomyopathy were observed in the Clozaril-treated group  Convulsions: 2.5% (N = 12) C

CBR-12 InterSePT Benefit Experience  Significantly lower risk of suicidal behavior relative to Zyprexa ® (P =.03)  26% reduction in risk of suicide attempts or hospitalizations to prevent suicide for Clozaril ® relative to Zyprexa C

CBR-13 Number Needed to Treat (NNT) to Prevent a Suicide Attempt  Clozaril ® has a 2-year NNT of 13 – If 13 at-risk patients were treated with Clozaril instead of Zyprexa ®, we would prevent 1 suicide attempt or 1 hospitalization to prevent suicide 8

CBR-14 Benefit Risk Calculation Risk in 2 years for every 1,000 patients on Clozaril ® RisksAgranulocytosis3.5 Myocarditis< 1 BenefitsNumber of patients for whom one suicide attempt, suicide, or hospitalization related to suicide, was prevented compared to treatment with Zyprexa ® 77

CBR-15 Conclusions  Suicidal behavior in patients with schizophrenia or schizoaffective disorder represents an important unmet medical need  InterSePT demonstrates the efficacy of Clozaril ® in reducing suicidal behavior in comparison with Zyprexa ®  Use of Clozaril for the proposed indication poses no additional safety risk  Clozaril should be an available treatment option for patients with suicidal behavior C